The retroviruses we study were isolated from wild mice and cause a non- inflammatory neurodegenerative disease in mice similar to that caused by the unconventional agents such as scrapie, but this disease does not involve the generation of "prion" protein. We are using this system as an animal model for studying the pathogenesis of retrovirus-induced neurodegeneration. This laboratory has divided its efforts into three areas: Identification of the viral sequences which mediate tempo and character of the neurovirulence; the host factors which are involved in susceptibility to disease; and the mechanisms involved in the induction of neuronal cytopathology. In the past year we have made considerable headway in all three areas. The disease as it appears in feral mice has a long incubation period of up to 1 year. Using molecular cloning techniques we have identified a 41 base sequence in the 5' leader of the viral genome which appears to be a primary determinant of incubation period. Initial studies indicate that this sequence functions by influencing the efficiency of virus spread in vivo. This sequences residues within an open reading frame for a glycosylated form of the gag polyprotein. Host factors are also involved in the determination of incubation period. We previously found that the CNS is susceptible to infection until the 10th day of age. We have recently found that the length of the incubation period is dependent on a dynamic relationship between this progressive age-dependent restriction of virus replication in the CNS and the rate of virus replication within peripheral organs. This finding has provided considerable insight into the host/virus interactions which determine the kinetics of this "slow virus" disease. We are continuing our efforts to uncover the pathogenetic mechanisms responsible for the neuronal cytopathology induced by the wild mouse retrovirus. Using microinjection techniques we were able to increase the number and expand the types of cells in the CNS which were infected. Yet the course of the disease was not changed from that seen in neonatally inoculated mice. Thus, it appears that the neurodegeneration induced by this virus requires that a particular stage of postnatal CNS development be attained. This observation, in addition to our previous finding that infected neurons exhibit no evidence of cytopathology and neurons exhibiting cytopathology appear not to be infected, suggest that the neurodegeneration is an indirect consequence of virus infection. Future research goals involve the search for a possible neurotoxin using known inhibitors of NMDA, kainate and quinolinic acid receptors. In addition, we plan to examine the possible role of microglial cell activation in this disease. We will continue our studies of the viral sequences which mediate neurovirulence. Identification of these sequences and their respective function should provide further insight into the pathogenesis of this neurodegenerative disease.